PROJECT SUMMARY / ABSTRACT
Patients with Short Bowel Syndrome (SBS) require intravenous nutrition via a process called Total
Parenteral Nutrition (TPN) as they cannot sustain nutritional needs through regular enteral nutrition (EN) due to
insufficient intestines. Worldwide, tens of thousands of patients require TPN. Unfortunately, side effects in SBS
include potentially fatal liver and gut injury from a likely multifactorial etiology.
While many prior studies have focused on the possible detrimental effects induced by TPN constituents,
we instead postulate the novel hypothesis that the state of luminal content deprivation as occurring in SBS alters
gut-systemic signals driving injury mechanisms. Further analyzing these pathways, using a novel ambulatory
SBS piglet model developed by us, which recapitulates human SBS (SLU#2346,43-R-011), we have shown gut
microbial shifts in SBS with a significant increase in the Bacteroidetes phylum and decrease in the Firmicutes
phylum as well as significant sub phylum changes. Pertinently, in SBS we have also published decreased
synthesis of hepato-protective Fibroblast Growth Factor 19 (FGF19) secondary to inadequate gut Farnesoid X
Receptor (FXR) activation and a decrease in the gut growth hormone, glucagon like peptide – 2 (GLP-2) due to
a lack of gut receptor TGR5 activation. Indeed, during normal enterohepatic circulation, primary bile acids (FXR
ligands), synthesized by the liver undergo transformation to secondary bile acids (TGR5 ligands) by the gut
microbiota and thus we highlight a novel mechanism by which gut microbes modulate bile acid signaling
properties and thus alter the course of injury in SBS. Thus, we note that an altered gut microbiota, has a
prominent role in driving injury in SBS and hypothesize that its restoration in SBS animals by intestinal microbiota
transplant (IMT), obtained from EN animals, will mitigate injury. Using our model, as proof of concept, we have
noted mitigation of hepatic and gut injury in SBS upon IMT, attesting to its therapeutic role.
As detailed in the research plan; with Aim 1 we will test the impact of rigorously monitored IMT to SBS
and evaluate gut injury. We shall objectively classify and quantify stool microbiota using culture-independent
targeted amplicon sequencing and shotgun metagenomics, assess serological gut injury markers, histology and
perform gut morphometric analysis to gain mechanistic insights. Aim 2 relates to assessing the impact of IMT in
SBS on hepatic injury. We will thus assess liver injury serological markers, hepato-toxic cytokine profiles and
liver histology to assess impact of IMT. Aim 3 will focus on understanding mechanisms along the gut-systemic
signaling axis driving injury in SBS. We will evaluate key hepatobiliary receptors, transporters and signaling
molecules along the FXR-FGF19 and TGR5-GLP-2 gut-systemic axis to gain insights into microbial modulators
and their mechanisms driving SBS injury.
This project, using a highly translatable SBS model will help advance strategies to mitigate serious
complications and provide critical insights into microbiota driven modulation of injury in SBS.